Oral formulations on an antifungal

ABSTRACT

The present invention concerns a formulation for oral administration comprising an antifungal, a sufficient amount of a cyclodextrin or a derivative thereof, an aqueous acidic medium as bulk liquid carrier and an alcoholic co-solvent Addition of one or more pharmaceutically acceptable sweeteners and one or more pharmaceutically acceptable flavors thereto yields palatable oral formulations. A process of preparing such formulations and pharmaceutical dosage forms comprising said formulations.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is based upon PCT application Ser. No. PCT/EP 94/03169,filed Sep. 22, 1994, which claims priority from U.S. patent applicationSer. No. 08/129,504, filed on Sep. 30, 1993 now abandoned.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is based upon PCT application Ser. No. PCT/EP 94/03169,filed Sep. 22, 1994, which claims priority from U.S. patent applicationSer. No. 08/129,504, filed on Sep. 30, 1993 now abandoned.

The present invention is concerned with novel compositions of antifungalagents which have low solubility in aqueous media, a process forpreparing said compositions and pharmaceutical dosage forms for oraladministration comprising said novel compositions.

The development of efficacious pharmaceutical compositions of azoleantifungals such as for example, itraconazole and saperconazole, ishampered considerably by the fact that said antifungals are only verysparingly soluble in water. The solubility and bioavailability of saidcompounds can be increased by complexation with cyclodextrins orderivatives thereof as described in WO 85/02767 and U.S. Pat. No.4,764,604. Alternatively, strongly acidic formulations (pH≦1.5) ofitraconazole and saperconazole can be formed in which the activeingredients are partially dissolved. Obviously such strongly acidicformulations are useless for oral administration. Aqueous formulationscomprising a co-solvent such as PEG 400 completely dissolve itraconazoleat pH 2.3-2.5. However, these acidic formulations have problems withregard to ease-of-preparation, acceptability, palatability andespecially bioavailability: upon administration said formulations canprecipitate irreversibly, e.g. in the stomach. Acidic formulationscomprising cyclodextrin or a derivative thereof might appear an obviousalternative, but the mere combinations prove to suffer from a number ofsimilar problems, in particular difficulty-of-preparation, lack ofstability (shelf life) and palatability, and unreliable absorption. Inshort, there still exists an important demand for easily preparedformulations of antifungal agents with good bioavailability andacceptable organoleptic properties for oral administration.

The present invention relates to formulations for oral administrationwhich comprise an antifungal, e.g. itraconazole or saperconazole, asactive ingredient, a sufficient mount of a cyclodextrin or a derivativethereof as a solubilizer, an aqueous acidic medium as bulk liquidcarrier and an alcoholic co-solvent that greatly simplifies thepreparation of the composition. Preferred formulations are rendered morepalatable by adding one or more pharmaceutically acceptable sweeteners,and one or more pharmaceutically acceptable flavours.

A low-dosage formulation according to the present invention is suitablefor treating patients suffering from fungal infections, particularly fortreating AIDS patients with oral candidiasis infections. The need forreliable formulations of itraconazole (and saperconazole) in thisindication is especially high because of resistance to fluconazoledeveloping in Candida strains. Generally, 400 mg/day represents theminimum dose required to obtain meaningful plasm levels. Suitable oralformulations typically comprise from about 0.5% to about 1.5% (w/v),preferably about 1% (w/v) of the active ingredient.

A high-dosage formulation according to the present invention is suitablefor treating patients suffering from systemic fungal infections.Suitable oral formulations for combatting systemic fungal infectionstypically comprise from about 3% to about 5%, preferably about 4% (w/v)of the active ingredient.

The formulations of the present invention are also suitable for thetreatment of fungal infections in non-human animals, in particular forthe treatment of dermatophytoses.

Itraconazole or (±)-cis-4- 4- 4- 4-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one,is a broadspectrum antifungal compound developed for oral, parenteraland topical use and is disclosed in U.S. Pat. No. 4,267,179. Itsdifluoro analog, saperconazole or (±)-cis-4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!-phenyl!-2,4-dihydro-2-(1-methoxypropyl)-3H-1,2,4-triazol-3-one,has improved activity against Aspergillus spp. and is disclosed in U.S.Pat. No. 4,916,134.

Appropriate cyclodextrin derivatives are α-, β-, γ-cyclodextrins orethers and mixed ethers thereof wherein one or more of the hydroxygroups of the anhydroglucose units of the cyclodextrin are substitutedwith C₁₋₆ alkyl, particularly methyl, ethyl or isopropyl; hydroxyC₁₋₆alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl;carboxyC₁₋₆ alkyl, particularly carboxymethyl or carboxyethyl; C₁₋₆alkylcarbonyl, particularly acetyl; C₁₋₆ alkyloxycarbonylC₁₋₆ alkyl orcarboxyC₁₋₆ alkyloxyC₁₋₆ alkyl, particularly carboxymethoxypropyl orcarboxyethoxypropyl; C₁₋₆ alkylcarbonyloxyC₁₋₆ alkyl, particularly2-acetyloxypropyl. Especially noteworthy as complexants and/orsolubilizers are β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD.

The term mixed ether denotes cyclodextrin derivatives wherein at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxypropyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of theaverage number of moles of alkoxy units per mole of anhydroglucose. Inthe cyclodextrin derivatives for use in the compositions according tothe present invention the M.S. is in the range of 0.125 to 10, inparticular of 0.3 to 3, or from 0.3 to 1.5. Preferably the M.S. rangesfrom about 0.3 to about 0.8, in particular from about 0.35 to about 0.5and most particularly is about 0.4. M.S. values determined by NMR of IRpreferably range from 0.3 to 1, in particular from 0.55 to 0.75.

The average substitution degree (D.S.) refers to the average number ofsubstituted hydroxyls per anhydroglucose unit. In the cyclodextrinderivatives for use in the compositions according to the presentinvention the D.S. is in the range of 0.125 to 3, in particular of 0.2to 2 or from 0.2 to 1.5. Preferably the D.S. ranges from about 0.2 toabout 0.7, in particular from about 0.35 to about 0.5 and mostparticularly is about 0.4. D.S. values determined by NMR of IRpreferably range from 0.3 to 1, in particular from 0.55 to 0.75.

More particular β- and γ-cyclodextrin hydroxyalkyl derivatives for usein the compositions according to the present invention are partiallysubstituted cyclodextrin derivatives wherein the average degree ofalkylation at hydroxyl groups of different positions of theanhydroglucose units is about 0% to 20% for the 3 position, 2% to 70%for the 2 position and about 5% to 90% for the 6 position. Preferablythe amount of unsubstituted β- or γ-cyclodextrin is less than 5% of thetotal cyclodextrin content and in particular is less than 1.5%. Anotherparticularly interesting cyclodexuin derivative is randomly methylatedβ-cyclodextrin.

Most preferred cyclodextrin derivatives for use in the present inventionare those partially substituted β-cyclodextrin ethers or mixed ethershaving hydroxypropyl, hydroxyethyl and in particular 2-hydroxypropyland/or 2-(1-hydroxypropyl) substituents.

The most preferred cyclodextrin derivative for use in the compositionsof the present invention is hydroxypropyl-β-cyclodextrin having a M.S.in the range of from 0.35 to 0.50 and containing less than 1.5%unsubstituted β-cyclodextrin. M.S. values determined by NMR or IRpreferably range from 0.55 to 0.75.

Substituted cyclodextrins can be prepared according to proceduresdescribed in U.S. Pat. No. 3,459,731, EP-A-0,149,197, EP-A-0,197,571,U.S. Pat. No. 4,535,152, WO-90/12035 and GB-2,189,245. Other referencesdescribing cyclodextrins for use in the compositions according to thepresent invention, and which provide a guide for the preparation,purification and analysis of cyclodextrins include the following:"Cyclodextrin Technology" by Jozsef Szejtli, Kluwer Academic Publishers(1988) in the chapter Cyclodextrins in Pharmaceuticals; "CyclodextrinChemistry" by M. L. Bender et at., Springer-Verlag, Berlin (1978);"Advances in Carbohydrate Chemistry", Vol. 12 Ed. by M. L. Wolfrom,Academic Press, New York (157) in the chapter The Schardinger Dextrinsby Dexter French at p. 189-260; "Cyclodextrins and their InclusionsComplexes" by J. Szejtli, Akademiai Kiado, Budapest, Hungary (1982); I.Tabushi in Acc. Chem. Research, 1982, 15, p. 66-72; W. Sanger,Angewandte Chemic, 92, p. 343-361 (1981); A. P. Croft and R. A. Bartschin Tetrahedron, 39, p. 1417-1474 (1983); Irie et al. PharmaceuticalResearch, 5, p. 713-716, (1988); Pitha et al. Int. J. Pharm. 29, 73,(1986); DE 3,118,218; DE-3,317,064; EP-A-94,157; U.S. Pat No. 4,659,696;and U.S. Pat. No. 4,383,992. The low-dosage oral formulations accordingto the present invention typically comprise from about 20% to about 60%(w/v), preferably about 40% (w/v) of the cyclodextrin. The high-dosageformulations typically comprise from about 50% to about 80% (w/v),preferably about 60% (w/v) of the cyclodextrin derivative.

In order to increase the rate of dissolution of the poorly solubleantifungal during the manufacturing process, an alcoholic co-solvent isemployed in the formulations according to the present invention. Forthis purpose, preference is given to those alcoholic co-solvents thathave good dissolving power for itraconazole and/or saperconazole, inparticular ethanol, propylene glycol and glycerol, especially propyleneglycol. Without the alcoholic co-solvent, the dissolution ofitraconazole or saperconazole in an aqueous acidic cyclodextrin mediumis very slow, requiring a viscous suspension to be stirred for aprohibitively long time until complete dissolution is obtained. Additionof the alcoholic co-solvent, in the range of about 1% (v/v) to about 20%(v/v), preferably about 10% (v/v), increases the dissolution rate of theantifungal agent in an aqueous acidic cyclodextrin medium by a factor ofat least 5 (when used at 10% (v/v)) and thus considerably shortens andsimplifies the production process.

As a bulk liquid carrier there is used an acidic aqueous medium.Preferably the acidity of said carrier derives from a strong,pharmaceutically acceptable acid such as hydrochloric acid. Thebioavailability of the antifungal agent and the organoleptic propertiesof the oral formulations are affected contrariwise by the acidity. Anoptimum effect can be obtained at pH 2.0±0.1: that is, at this pH value,a sufficiently stable and bioavailable antifungal formulation isobtainable, the organoleptic properties of which can be renderedacceptable.

Not surprisingly, the ingredients thus far described yield a fairlystrong-tasting potion when mixed with one another. Besides the acidtaste due to the low pH, a bitter taste originating from the activeingredient, and possibly from the co-solvent (e.g. in the case ofpropylene glycol), is also present. Optimum taste masking can beobtained by the use of two types of adjuvants, namely pharmaceuticallyacceptable sweeteners and flavours. Sweeteners are the more importantadditives in the low-dosage formulations, whereas the flavours are moreimportant in the high-dosage formulations.

The pharmaceutically acceptable sweeteners comprise preferably at leastone intense sweetener such as saccharin, sodium or calcium saccharin,aspartame, acesulfame potassium, sodium cyclamate, alitame, adihydrochalcone sweetener, monellin, stevioside or sucralose(4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose), preferablysaccharin, sodium or calcium saccharin, and optionally a bulk sweetenersuch as sorbitol, mannitol, fructose, sucrose, maltose, isomalt,glucose, hydrogenated glucose syrup, xylitol, caramel or honey.

The intense sweetener is conveniently employed in low concentrations.For example, in the case of sodium saccharin, the concentration mayrange from 0.04% to 0.1% (w/v) based on the total volume of the finalformulation, and preferably is about 0.06% in the low-dosageformulations and about 0.08% in the high-dosage ones. The bulk sweetenercan effectively be used in larger quantities ranging from about 10% toabout 35%, preferably from about 10% to 15% (w/v). In the high-dosageformulations the cyclodextrin derivative behaves as a bulk sweetener andnone of the aforementioned bulk sweeteners needs to be added.

The pharmaceutically acceptable flavours which can mask the bittertasting ingredients in the low-dosage formulations are preferably fruitflavours such as cherry, raspberry, black currant or strawberry flavour.A combination of two cherry flavours was found to yield very goodresults in an itraconazole formulation both as regards physico-chemicalstability as well as regards organoleptic acceptability. In thehigh-dosage formulations stronger flavours are required such as CaramelChocolate flavour, Mint Cool flavour, Fantasy flavour and the likepharmaceutically acceptable strong flavours. Each flavour may be presentin the final composition in a concentration ranging from 0.05% to 1%(w/v). Combinations of said strong flavours are advantageously used.Preferably a flavour is used that does not undergo any change or loss oftaste and colour under the acidic conditions of the formulation.

A preferred high-dosage formulation according to the present inventioncomprises by weight or by volume based on the total volume of theformulation:

(a) 4% (w/v) itraconazole;

(b) 60% (w/v) hydroxypropyl-β-cyclodextrin;

(c) 10% (v/v) propylene glycol;

(d) acid and base to adjust the pH of the composition within the rangeof 2.0±0.1;

(e) 0.08% (w/v) sodium saccharin;

(f) up to 1% (w/v) of one or more strong flavours; and

(g) water.

The preparation of the formulations according to the present inventionwill hereafter be described with regard to a preferred low-dosageformulation having the following composition (% are by weight or byvolume based on the total volume of the formulation):

(a) 1% (w/v) itraconazole;

(b) 40% (w/v) hydroxypropyl-β-cyclodextrin;

(c) 10% (v/v) propylene glycol;

(d) acid and base to adjust the pH of the composition within the rangeof 2.0±0.1;

(e) 0.06% (w/v) sodium saccharin;

(f) 19% (v/v) sorbitol (70%) non-crystallizing solution;

(g) up to 1% (w/v) of one or more cherry flavours; and

(h) water.

Optionally, the above preferred low-dosage formulation further comprisesup to 0.1%, in particular 0.02% caramel sweetener.

Similar formulations can be prepared with saperconazole, though otherflavours may be preferred then.

Said process of preparation comprises the steps of

(a) dissolving the active ingredient in the alcoholic co-solvent andacid;

(b) dissolving the cyclodextrin in water and adding thereto the solutionprepared in

(a) while stirring until homogenous;

(c) adding the sweetener(s) and the flavour(s);

(d) adjusting the acidity to pH 2.0±0.1 and

(e) diluting the formulation to the desired end-volume.

In particular, for preparing 1 liter of the aforementioned preferredformulation 100 ml of propylene glycol is treated with 3.76 mlconcentrated HCl, stirred and slightly heated. 10 g itraconazole isadded and stirring is continued until homogeneous.

In a separate vessel, 400 g hydroxypropyl-β-cyclodextrin is dissolved in400 ml distilled water. The solution of the active ingredient is addedslowly to the cyclodextrin solution while stirring. The sorbitolsolution (190 ml) is added and stirred till homogeneous. The sodiumsaccharin (0.6 g) is dissolved in 50 ml distilled water and added to themixture. The flavours are added and the pH of the mixture (about 1.7) isadjusted with a 10N NaOH solution to pH 2.0±0.1. The resulting solutionis diluted with distilled water to an end volume of 1 liter. Apharmaceutical dosage form is obtained by filtering the previoussolution and filling it into suitable containers. e.g. in 100 ml glassbottles with a screw cap. The pharmaceutical dosage form advantageouslycomprises a minimal volume of air above the solution, preferably aninert gas such as nitrogen. Besides the exclusion of air (oxygen),storage at temperatures below 25° C. also beneficially affects themaximum shelf life of the formulation for oral administration.

In case a more simple formulation lacking the flavour(s) and/orsweetener(s) is envisaged, step (c) is omitted partially or completelyfrom the process of preparation.

We claim:
 1. A formulation for oral administration comprising:(a)itraconazole or saperconazole; (b) a sufficient amount of ahydroxypropyl-β-cyclodextrin having an M.S. in the range of 0.3 to 3 andcontaining less than 5% unsubstituted β-cyclodextrin, to act as asolubilizer for the itraconazole or saperconazole; (c) an aqueous acidicmedium as bulk liquid carrier; (d) from about 1% (v/v) to about 20%(v/v) of an alcoholic co-solvent selected from the group consisting ofethanol, propylene glycol and glycerol; (e) one or more pharmaceuticallyacceptable intense sweeteners plus one or more bulk sweeteners; and (f)one or more pharmaceutically acceptable flavors.
 2. A formulationaccording to claim 1 wherein the cyclodextrin ishydroxypropyl-β-cyclodextrin having an M.S. in the range of 0.35 to 0.50and containing less than 1.5% unsubstituted β-cyclodextrin.
 3. Aformulation according to claim 2 wherein the alcoholic co-solvent ispropylene glycol.
 4. A formulation according to claim 3 having a pH of2.0±0.1.
 5. A formulation according to claim 4 wherein the intensesweetener is selected from the group consisting of saccharin, sodium orcalcium saccharin and the bulk sweetener is selected from the groupconsisting of sorbitol, mannitol, fructose, sucrose, maltose, glucose,caramel or honey.
 6. A formulation according to claim 1 comprising byweight or by volume based on the total volume of the formulation:(a) 4%(w/v) itraconazole; (b) 60% (w/v) hydroxypropyl-β-cyclodextrin; (c) 10%(v/v) propylene glycol; (d) acid and base to adjust the pH of thecomposition within the range of 2.0±0.1; (e) 0.08% (w/v) sodiumsaccharin; (f) up to 1% (w/v) of one or more flavours; and (g) water. 7.A formulation according to claim 1 comprising by weight or by volumebased on the total volume of the formulation:(a) 1% (w/v) itraconazoleor saperconazole; (b) 40% (w/v) hydroxypropyl-β-cyclodextrin; (c) 10%(v/v) propyleneglycol; (d) acid or base to adjust the pH of thecomposition within the range of 2.0±0.1; (e) 0.06% (w/v) sodiumsaccharin; (f) 19% (v/v) sorbitol (70%) non-crystallizing solution; (g)up to 1% (w/v) of one or more flavours; (h) 0.02% (w/v) of a carmelsweetener; and (i) water.